The treatment of cancer by radio-immunotherapy involves injecting the patient with a radioactive isotope ‘bullet’ connected to a specific cancer cell vector such as a monoclonal antibody, with the aim of selectively destroying targeted tumour cells. During radioactive decay, photons, electrons or even heavier particles are emitted and damage or kill cells along their trajectory.
Radio-immunotherapy (RIT) is still a relatively new modality for cancer therapy, which started using beta-emitting radionuclides. These have a relative low linear energy transfer (LET) and a long range in tissues, so their decay energy is only partially absorbed by the cancerous cells; the remainder attacks healthy cells in an undesirable manner.
As a result, the focus of research shifted to radionuclides emitting alpha particles, which have high linear energy transfer values and release their energy over just a few cell diameters. Recent experiments have proved alpha emitters to be very effective in destroying tumour cells. They are considered to be especially attractive for the treatment of blood-borne cancers and micrometastatic tumours (where cancer cells are typically present throughout the body). Another likely area of use for alpha-immunotherapy is in treating the small numbers of cancer cells that may remain after high-dose chemotherapy or surgery.
RIT is performed by administering to cancer patients so-called radioimmunoconjugates, which are constructs comprising a radionuclide with desirable properties linked to an antibody. Generally, the linking of the radionuclide to the antibody is done by means of a chelating agent. In the body, the antibody will carry the radionuclide to a diseased tissue expressing a corresponding antigen.
To date, a variety of alpha-emitting radionuclides have been used for RIT and more particularly: terbium-149 (Tb-149), astatine (At-211), bismuth-212 (Bi-212), bismuth-213 (Bi-213) and actinium-225 (Ac-225). Furthermore, a variety of chelating agents and antibodies, especially monoclonal antibodies, have been developed.
The development of radioimmunoconjugates involves adequate selections of radionuclides, targeting moieties and chelators. When designing a radioimmunoconjugate for RIT, numerous parameters have to be taken into account, in particular the targeting specificity of the antibody to the cells to be targeted, the cytotoxic potentiality of the selected radionuclide with regard to the targeted cells and the stability of the antibody-radionuclide link by the chelator. The design of radioimmunoconjugates is thus a complex matter and the actual efficiency of a radioimmunoconjugate can in fact only be validated by testing in pre-clinical and clinical trials.
Among the radionuclides, Bi-213 is currently widely used in RIT. This radionuclide decays mainly (98%) by β- and 440 keV γ emission with a half-life of 45.6 minutes to the ultra-short lived high-energy (8.375 MeV) alpha-emitter polonium-213 (t1/2 of 4 μs), whereas a direct alpha-decay pathway to thallium-209 plays only a negligible role (2% of all Bi-213 decays).
U.S. Pat. No. 5,641,471 discloses a method for preparing Bi-213 for therapeutic use, wherein a monoclonal antibody is used as targeting moiety. A chelator such as CHX-DTPA (cyclohexyldiethylenetriamine pentaacetic acid) is attached to the antibody and functions to chelate the radionuclide. In this manner, the radioisotope is delivered to the target cell where it can function in a therapeutic manner to destroy it.
U.S. Pat. No. 5,246,691 discloses radioimmunotherapy using Ac-225 and its daughters as part of a radioimmunoconjugate also comprising an antibody such as human monoclonal antibody and humanized antibodies.
Many references have described the use of radioimmunoconjugates comprising a radionuclide linked to a monoclonal antibody by a chelator. Although increasing efforts are made in RIT and despite the growth of monoclonal antibodies used in clinical trials, there is a continuous need for radioimmunoconjugates providing efficient therapeutic effects in cancer therapy.